TY - JOUR
T1 - Directly linked soluble IL-6 receptor-IL-6 fusion protein induces astrocyte differentiation from neuroepithelial cells via activation of STAT3
AU - Takizawa, Takumi
AU - Yanagisawa, Makoto
AU - Ochiai, Wataru
AU - Yasukawa, Kiyoshi
AU - Ishiguro, Takahiko
AU - Nakashima, Kinichi
AU - Taga, Tetsuya
N1 - Funding Information:
We wish to thank Dr K Ikenaka for GFAP promoter-containing reporter construct, Drs K. Shimozaki and S. Nagata for pEF-Rluc, Drs M. Minami and S. Akira for DN-STAT3-expressing construct, and Dr T. Hisatsune for valuable discussion on neuroepithelial cell culture. We are very grateful to Ms Y. Nakamura for her excellent secretarial assistance. We also thank Mr R. Watabe for technical help. This work has been supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan, Human Frontier Science Program, Ichiro Kanehara Foundation, Inamori Foundation, Kato Memorial Bioscience Foundation, and Naito foundation.
PY - 2001/3/7
Y1 - 2001/3/7
N2 - Signals of interleukin 6 (IL-6) are transduced by binding of IL-6 to its cell surface receptor (IL-6R) and subsequent association of the resultant IL-6/IL-6R complex with gp130, the signal transducing receptor component utilized in common by all the IL-6 family of cytokines. A soluble form of IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic regions, retains the ability to bind IL-6 and signal through gp130. We show here that a fusion protein of sIL-6R and IL-6 without a polypeptide linker, termed FP6, induces differentiation of astrocytes from fetal mouse neuroepithelial cells as potently as a representative IL-6 family cytokine, leukaemia inhibitory factor (LIF). FP6 has a potential to activate a transcription factor, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases, ERK1 and ERK2, in these cells as does LIF. FP6 activates a promoter of the gene for an astrocytic marker, glial fibrillary acidic protein (GFAP), in neuroepithelial cells. This activation is virtually abolished by ectopic expression of a dominant-negative form of STAT3, or by introducing a point mutation into the STAT3 response element located in the GFAP promoter. These results suggest that FP6 induces astrocyte differentiation from neuroepithelial cells through STAT3 activation and that FP6 could be of use as a substitute for natural IL-6 family cytokines.
AB - Signals of interleukin 6 (IL-6) are transduced by binding of IL-6 to its cell surface receptor (IL-6R) and subsequent association of the resultant IL-6/IL-6R complex with gp130, the signal transducing receptor component utilized in common by all the IL-6 family of cytokines. A soluble form of IL-6R (sIL-6R), which lacks transmembrane and cytoplasmic regions, retains the ability to bind IL-6 and signal through gp130. We show here that a fusion protein of sIL-6R and IL-6 without a polypeptide linker, termed FP6, induces differentiation of astrocytes from fetal mouse neuroepithelial cells as potently as a representative IL-6 family cytokine, leukaemia inhibitory factor (LIF). FP6 has a potential to activate a transcription factor, signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases, ERK1 and ERK2, in these cells as does LIF. FP6 activates a promoter of the gene for an astrocytic marker, glial fibrillary acidic protein (GFAP), in neuroepithelial cells. This activation is virtually abolished by ectopic expression of a dominant-negative form of STAT3, or by introducing a point mutation into the STAT3 response element located in the GFAP promoter. These results suggest that FP6 induces astrocyte differentiation from neuroepithelial cells through STAT3 activation and that FP6 could be of use as a substitute for natural IL-6 family cytokines.
UR - http://www.scopus.com/inward/record.url?scp=0035819764&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035819764&partnerID=8YFLogxK
U2 - 10.1006/cyto.2000.0831
DO - 10.1006/cyto.2000.0831
M3 - Article
C2 - 11243705
AN - SCOPUS:0035819764
VL - 13
SP - 272
EP - 279
JO - Cytokine
JF - Cytokine
SN - 1043-4666
IS - 5
ER -